A primary function of the immune response is to discriminate self from non-self antigens and to eliminate the latter. The immune response involves complex cell to cell interactions and depends primarily on three major cell types: thymus derived (T) lymphocytes, bone marrow derived (B) lymphocytes, and macrophages. The immune response is mediated by molecules encoded by the major histocompatibility complex (MHC). The two principal classes of MHC molecules, Class I and Class II, each comprise a set of cell surface glycoproteins ("Basic and Clinical Immunology" (1991) Stites, D. P. and Terr, A. I. (eds), Appelton and Lange, Norwalk, Conn./San Mateo, Calif.). MHC Class I molecules are found on virtually all somatic cell types, although at different levels in different cell types. In contrast, MHC Class II molecules are normally expressed only on a few cell types, such as lymphocytes, macrophages and dendritic cells.
Antigens are presented to the immune system in the context of Class I or Class II cell surface molecules; CD4.sup.+ helper T-lymphocytes recognize antigens in association with Class II MHC molecules, and CD8.sup.+ cytotoxic lymphocytes (CTL) recognize antigens in association with Class I gene products. It is currently believed that MHC Class I molecules function primarily as the targets of the cellular immune response, whereas the Class II molecules regulate both the humoral and cellular immune response (Klein, J. and Gutze, E., (1977) "Major Histocompatibility Complex" Springer Verlag, New York; Roitt, I. M. (1984) Triangle, (Engl Ed) 23:67-76; Unanue, E. R. (1984) Ann. Rev. Immunology, 2:295-428). MHC Class I and Class II molecules have been the focus of much study with respect to research in autoimmune diseases because of their roles as mediators or initiators of the immune response. MHC-Class II antigens have been the primary focus of research in the etiology of autoimmune diseases, whereas MHC-Class I has historically been the focus of research in transplantation rejection.
Graves' disease is a relatively common autoimmune disorder of the thyroid. In Graves' disease, autoantibodies against thyroid antigens, particularly the thyrotropin receptor, alter thyroid function and result in hyperthyroidism ("Basic and Clinical Immunology" (1991) Stites, D. P. and Terr, A. I. (eds), Appelton and Lange, Norwalk, Conn./San Mateo, Calif.: pages 469-470). Thyrocytes from patients with Graves' disease have aberrant MHC-Class II expression and elevated MHC Class I expression. (Kohn et al., (1992) In "International Reviews of Immunology," Vol 912:135-165).
Thionamide therapy has historically been used to treat Graves' disease. The most commonly used thionamides are methimazole (MMI), carbimazole (CBZ) and propylthiouracil (PTU). These thionamides contain a thiourea group; the most potent are thioureylenes (W. L. Green (1991) In Werner and Ingbar's "The Thyroid": A Fundamental Clinical Text" 6th edition, L. Braverman and R. Utiger (eds), J. B. Lippincott Co. page 324). The thionamides restore a euthyroid state by inhibiting thyroid peroxidase catalyzed formation of the thyroid hormones produced by the thyroid stimulating autoantibody stimulated thyroid (Solomon, D. H. (1986) In "Treatment of Graves' Hyperthyroidism". Ingbar, S. H., Braverman, L. E. (eds) The Thyroid: JB Lippincott Co., Philadelphia, Pa., p. 987-1014; Cooper, D. S. (1984) N. Engl. J. Med., 311: 1353-1362; Cooper, D. S. (1991) Treatment Of Thyrotoxicosis. In Werner And Ingbar's The Thyroid: A Fundamental and Clinical Text," 6th edition. L. Braverman and R. Utiger (eds), J. B. Lippincott Co. pages 887-916). It has been reported that MMI and PTU can inhibit peroxidase-dependent enzymes in the kidney and that MMI can inhibit gastric peroxidase in rat gastric mucosa (Zelman, S. J. et al., (1984) J. Lab. Clin. Med. 104:185-192; Bandyopadhyay, U. et al., (1992) Biochem J. 284:305-312). PTU has also been reported to inhibit hepatoxicity associated with alcoholism (Orrego, H. et al., (1987) N. Engl. J. of Med. 317:1421-1427). Thionamides have been used to treat Graves' patients for extended periods of time with the majority of patients experiencing no complication related to this therapy (Cooper, D. S. (1991) Treatment Of Thyrotoxicosis. In Werner And Ingbar's The Thyroid: A Fundamental and Clinical Text," 6th edition. L. Braverman and R. Utiger (eds), J. B. Lippincott Co. pages 887-916). Allergic reactions, including such symptoms as fever, rash, urticaria, occur in 1-5% of patients. Toxic reactions to thionmide treatments are rare, occurring in only 0.2 to 0.5% of the patients (Cooper, D. S. (1991) Treatment Of Thyrotoxicosis. In Werner And Ingbar's The Thyroid: A Fundamental and Clinical Text," 6th edition. L. Braverman and R. Utiger (eds), J. B. Lippincott Co. pages 887-916).
In addition to the effect of thionamides on thyroid hormone synthesis, it was recognized that thionamide therapy in Graves' disease was associated with a reduction in thyroid autoantibodies (Cooper, D. S. (1982) N. Clin. Endocrinol, Metab. 29:231-238; Kuzuya, N. et al., J. Clin. Endocrinol. Metab. 48:706-714; Bech, K. and Madsen, S. N. (1980) Clin Endocrinol (Oxf) 13:417-26; Hallengren, B. et al. (1980) J. Clin. Endocrinol. Metab 51:298-301; Cooper, D. S. (1991) Treatment Of Thyrotoxicosis. In Werner And Ingbar's "The Thyroid: A Fundamental and Clinical Text," 6th edition. L. Braverman and R. Utiger (eds), J. B. Lippincott Co. pages 887-916). Studies on the mechanism by which thionamides exert this effect are contradictory. One hypothesis suggests that the thionamides act directly on thyroid follicular cells and that the subsequent modulation in thyroid activity results in the immune effects (Volpe et al., (1986) Clin. Endocrinol. 25:453-462). A second hypothesis suggests that thionamides act directly on lymphocytes, particularly thyroid lymphocytes (Weetman, A. P. (1992) Clin Endocrinol. 37:317-318; McGregor, A. M. (1980) Brit. Med. J., 281:968-969). It has also been suggested that MMI interferes with antigen handling by accessory cells because these cells possess a peroxidase enzyme system (Weetman, A. P. (1983) Clin. Immuno. and Immunopath, 28:39-45). The current consensus appears to be that the therapeutic action of the thionamides, including the immunosuppressive effects, is thyroid specific and intrathyroidal (D. S. Cooper (1991) Treatment Of Thyrotoxicosis. In Werner And Ingbar's The Thyroid: A Fundamental and Clinical Text," 6th edition. L. Braverman and R. Utiger (eds), J. B. Lippincott Co. pages 888-889).
Results of studies involving the use of MMI in the treatment of diabetes are also contradictory. Hibbe, T. et al., (1991); Diabetes Res. and Clin. Practice 11:53-58, report that MMI enhances the development of streptozotocin-mediated diabetes in mice. In contrast, Waldhausl, W. et al. (1987) Akt. Endokrin. Stoffw. 8, 119 (abstract) report enhanced remission in 54% of 11 patients treated with MMI shortly after diagnosis of type I diabetes, basing their therapy on reputed effects of MMI on T helper cells. These authors reported no change in the levels of Class I and Class II antigens and it is unclear whether the effect was due to MMI or natural remission of the disease over the 9 month "honeymoon" period. In the BB rat, MMI depressed spontaneous development of thyroiditis but did not reduce the incidence of diabetes (Allen, F. M. et al., (1986) Am. J. Med. Sci., 292: 267-271; Braverman, L. E. et al., (1987) Acta. Endocrinol, (Coppenhagen) Suppl. 281: 70-76).
Saji, M. et al. (1992a); Proc. Natl. Acad. Sci. U.S.A. 89:1944-1948 describe hormonal regulation of MHC-class I genes in the rat thyroid cell line, FRTL-5. Treatment of the FRTL-5 cell line with thyroid stimulating hormone (TSH) resulted in decreased transcription of MHC class I DNA and reduced cell surface levels of MHC Class I antigens. Recently, a report by Saji, M. et al., (1992b) J. Clin. Endocrinol. Metab. 75:871-878, demonstrated that agents such as serum, insulin, insulin-like growth factor-I (IGF-1), hydrocortisone and thyroid stimulating thyrotropin receptor autoantibodies from Graves' patients decrease MHC-Class I gene expression in that FRTL-5 cells. In addition, treatment of the FRTL-5 cells with MMI or high doses of iodide resulted in decreased MHC Class I gene expression. The effect of MMI on reduction of MHC Class I expression was shown to be at the level of transcription and was additive with thyroid stimulating hormone and other hormones which normally suppress Class I in these cells. Saji, M. et al. (1992b) J. Clin. Endocrinol. Metab. 75:871-878, suggest a new mechanism by which MMI may act in the thyroid during treatment of Graves' disease; no extrapolation was made to any other autoimmune diseases. Prior to these studies it was known that Rous sarcoma virus, adenoviruses 12 and 2 and certain Gross viruses reduced expression of MHC Class I; however, SV40, Rad LV, and Mo MuLV viruses can increase Class I MHC expression (Singer & Maguire (1990) Crit. Rev. in Immun. 10:235-257).
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that, like Graves', has a relatively high rate of occurrence. SLE affects predominantly women, the incidence being 1 in 700 among women between the ages of twenty and sixty ("Cellular and Molecular Immunology (1991) Abbus, A. K., Lichtman, A. H., Pober, J. S. (eds); W. B. Saunders Company, Philadelphia: page 360-370). SLE is characterized by formation of a variety of autoantibodies and by multiple organ system involvement ("Basic and Clinical Immunology" (1991) Stites, D. P. and Terr, A. I. (eds), Appelton and Lange, Norwalk, Conn./San Mateo, Calif.: pages 438-443). Current therapies for treating SLE involve the use of corticosteroids and cytotoxic drugs, such as cyclosporin. Immunosuppressive drugs such as cyclosporin, FK506, or rapamycin suppress the immune system by reducing T cell numbers and function (Morris, P. J. (1991) Curr. Opin. in Immun., 3:748-751). While these immunosuppressive therapies alleviate the symptoms of SLE, and other autoimmune diseases, they have numerous severe side effects. In fact, extended therapy with these agents may cause greater morbidity than the underlying disease.
Women suffering from SLE who have breast cancer face particular difficulties. These individuals are immunosuppressed as a result of corticosteroid and cytotoxic drug treatment for SLE; radiotherapy for the treatment of the cancer would additionally enhance the immunosuppressed state. Further, radiation therapy, a current method of choice can exacerbate disease expression or induce severe radiation complications. For these individuals, alternative therapies that would allow for simultaneous treatment of SLE and the cancer are greatly needed.
As is true for autoimmune diseases, there is a great need for different ways of treating or preventing transplantation rejection. Transplantation rejection occurs as a result of histoincompatibility between the host and donor; it is the major obstacle in successful transplantation of tissues. Current treatment for transplantation rejection, as for autoimmune disease, involves the use of a variety of immunosuppressive drugs and corticosteroid treatment.
Faustman et al., (PCT International Application No. 92/04033) identify a method for inhibiting rejection of a transplanted tissue in a recipient animal by modifying, eliminating, or masking the antigens present on the surface of the transplanted tissue. Specifically, this application suggests modifying, masking, or eliminating human leukocyte antigen (HLA) Class I antigens. The preferred masking or modifying drugs are F(ab)' fragments of antibodies directed against HLA-Class I antigens. However, the effectiveness of such a therapy will be limited by the hosts' immune response to the antibody serving as the masking or modifying agent. In addition, in organ transplantation this treatment would not affect all of the cells because of the perfusion limitations of the masking antibodies. Faustman et al. disclose that fragments or whole viruses be transfected into donor cells, prior to transplantation into the host, to suppress HLA Class I expression. Use of whole or fragments of virus presents potential complications to the recipient of such transplanted tissue since some viruses, SV40 in particular, can increase Class I expression (Singer and Maguire (1990) Crit. Rev In Immunol. 10:235-237, TABLE 2).
Durant et al. (British Patent No. 592, 453) identify isothiourea compositions that may be useful in the treatment of autoimmune diseases and host versus graft (HVG) disease and assays for assessing the immunosuppressive capabilities of these compounds. However, this study does not describe MMI or the suppression of MHC Class I molecules in the treatment of autoimmune diseases.
U.S. Pat. Nos. 5,010,092 and 5,097,441 describe a method for reducing nephrotoxicity resulting from administration of an antibiotic in a mammal by coadministration of the antibiotic with either MMI or CBZ. These patents neither suggest nor teach the use of MMI to suppress MHC Class I expression in the treatment of autoimmune diseases or in the treatment and prevention of transplantation rejection.